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Iron: An emerging target for HF
Recent data demonstrate benefits of IV iron in patients with HFrEF.
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Data continue to accumulate on the outcomes associated with iron supplementation in patients with HF. Research presented at the American Heart Association Scientific Sessions in November 2016 highlighted improvements in exercise capacity and HF symptoms after supplementation with IV iron — but not oral iron — in patients with HF with reduced ejection fraction and iron deficiency.
“Iron seems to be emerging as a very important target in patients with HF with reduced EF and iron deficiency, but oral iron does not adequately replete iron stores,” Gregory D. Lewis, MD, section head of heart failure; director of the cardiopulmonary exercise testing laboratory and medical director of the cardiology ICU and mechanical circulatory support program at Massachusetts General Hospital; and assistant professor of medicine at Harvard Medical School, told Cardiology Today.
At AHA 2016, Lewis reported findings from the NIH-sponsored IRONOUT-HF study, a comparison of oral iron polysaccharide vs. oral placebo over 16 weeks in patients with HFrEF and iron deficiency. Dirk J. van Veldhuisen, MD, PhD, FESC, FACC, professor and chief of cardiology at University Medical Center Groningen, Netherlands, presented the EFFECT-HF study, sponsored by Vifor Pharma Ltd., which compared IV ferric carboxymaltose with the standard of care over 24 weeks in a similar population.
“A substantial proportion of patients with HF have iron deficiency anemia, which may influence their clinical course through suboptimal oxygen uptake and distribution,” Cardiology Today Editorial Board member Jagmeet P. Singh, MD, DPhil, FACC, FHRS, associate chief of the cardiology division at Massachusetts General Hospital Heart Center, Roman W. DeSanctis Endowed Chair in Cardiology and professor of medicine at Harvard Medical School, said in an interview.
IRONOUT-HF
Based on results from the FAIR-HF and CONFIRM-HF studies, Lewis and colleagues hypothesized that oral iron polysaccharide would be superior at 16 weeks to placebo in the primary outcome of improvement of peak VO2 in 225 patients with HFrEF and iron deficiency (median age, 63 years; 36% women; mean left ventricular EF, 25%).
“Oral iron is readily available, it’s inexpensive, you can get it at the drugstore and take it with your other pills,” Lewis said. “IV iron is different: You need to get an infusion [and] it’s expensive.”
There was no difference between oral iron and placebo in the primary endpoint, whether measured as change in peak VO2 in mL/min (median treatment difference, 21 mL/min; interquartile range, –34 to 76; P = .46) or in mL/kg/min (median treatment difference, 0.3 mL/kg/min; interquartile range, –0.27 to 0.87; P = .3).
There were no significant differences between the groups in any secondary endpoints (see Table).
The groups had similar rates of adverse events, serious adverse events, permanent study drug discontinuation and death or CV rehospitalization.
Of interest, Lewis told Cardiology Today, “We found an inappropriate elevation in hepcidin levels was directly related to the amount of iron repletion that people achieved. Those that had the highest levels of hepcidin had zero changes in their iron stores. Those that had the lowest appropriate levels did have some absorption of iron. That may give us insight going forward into people who might actually respond to oral iron.”
Singh agreed that the hepcidin findings were the most important contribution of IRONOUT-HF.
“Interestingly, the investigators showed that hepcidin may play a role in the biological mechanism that does not allow iron to enter the body, and could thereby explain the nonresponsiveness to oral iron,” he said.
EFFECT-HF
Van Veldhuisen and colleagues randomly assigned 174 patients (mean age, 63 years; 25% women; mean LVEF, 32%) to receive IV ferric carboxymaltose or the standard of care as determined by the individual physician.
The primary outcome was change in weight-adjusted peak VO2 from baseline to 24 weeks. Secondary outcomes included change in peak VO2 from baseline to 12 weeks, change in VE/VCO2 slope from baseline to 12 and 24 weeks, change in work rate achieved in peak exercise from baseline to 12 and 24 weeks, and changes in various biomarkers.
According to the researchers, the IV ferric carboxymaltose group had a greater change than the standard-of-care group in the primary outcome in both the full-analysis cohort (P = .02) or the per-protocol cohort (P = .01) (See Table for secondary outcomes).
Adverse event rates were similar between the groups.
“These findings confirm and extend the results of previous studies ... that treatment with ferric carboxymaltose improves exercise capacity and symptoms. Ferric carboxymaltose was well-tolerated in this patient population,” van Veldhuisen said during the presentation.
More research needed
Mary Norine Walsh, MD, FACC, medical director of heart failure and cardiac transplantation at St. Vincent Heart Center in Indianapolis, president-elect of the American College of Cardiology and a member of the Cardiology Today Editorial Board, said at least one larger trial in a more diverse population is needed before any definitive conclusions can be drawn about iron supplementation in patients with HFrEF and iron deficiency.
“We need a large randomized controlled trial of IV iron in HF,” she said. “While there is a signal there that we need to pursue, it was interesting that despite the fact that anemia in HFrEF is more prevalent in women, there were relatively few women in these trials. That’s where the money is, in treating women.”
A trial of IV ferric carboxymaltose (Injectafer, Luitpold Pharmaceuticals) vs. placebo in approximately 3,000 patients with HFrEF and iron deficiency is expected to launch soon. The primary endpoint is a hierarchical composite of death, HF hospitalization and change in 6-minute walk test at 12 months.
Lewis agreed that more studies with IV iron, perhaps enhanced by the new learnings about hepcidin, are necessary.
“We know that peak exercise capacity is highly related to mortality and HF,” he said. “Both studies suggest iron is a really important target, but it’s not going to be as simple as buying pills over the counter.” – by Erik Swain
- References:
- Lewis GD, et al.
- van Veldhuisen DJ, et al. LBCT.04 – Guiding the Momentum to Effect HF Outcomes – Ironing Out the Wrinkles. Both presented at: American Heart Association Scientific Sessions; Nov. 12-16, 2016; New Orleans.
- For more information:
- Gregory D. Lewis, MD, can be reached at Cardiac Unit Associates, 55 Fruit St., Boston MA, 02114; email: glewis@partners.org.
- Jagmeet P. Singh, MD, DPhil, FACC, FHRS, can be reached at Massachusetts General Hospital Heart Center, 55 Fruit St., Boston, MA 02114; email: jsingh@mgh.harvard.edu.
- Dirk J. van Veldhuisen, MD, PhD, FESC, FACC, can be reached at Department of Cardiology, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, PO Box 30.001, 9700, RB, Groningen, the Netherlands; email: d.j.van.veldhuisen@umcg.nl.
- Mary Norine Walsh, MD, FACC, can be reached at 8333 Naab Road #400, Indianapolis, IN 46260; email: macwalsh@iquest.net.
Disclosures: The EFFECT-HF study was sponsored by Vifor Pharma. Lewis and Walsh report no relevant financial disclosures. Singh reports consulting for Biotronik, Boston Scientific, Impulse Dynamics, Medtronic, Respicardia and St. Jude Medical. Van Veldhuisen reports receiving board membership fees and travel expenses from Vifor Pharma.